Clinical endocrinology · 2011
Aromatase deficiency owing to a functional variant in the placenta promoter and a novel missense mutation in the CYP19A1 gene.
Клинический случайСтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Hauri-Hohl Annik, Meyer-Böni Monika, Lang-Muritano Mariarosaria, Hauri-Hohl Mathias, Schoenle Eugen J, Biason-Lauber Anna
Аннотация
CONTEXT: Aromatase deficiency in women is a rare 46, XX disorder of sex differentiation characterized by a defect in catalysing oestrogens from androgens.
OBJECTIVE: To better understand this rare disorder, we searched for mutations in the CYP19A1 gene of an affected girl and analysed their functional consequences.
DESIGN AND PATIENT: We examined a girl presenting with clitoral hypertrophy at birth and mild maternal virilization (acne) during pregnancy.
MAIN OUTCOME MEASUREMENT: A genotype-phenotype correlation was found.
RESULTS: By direct sequencing of the CYP19A1 gene, we identified a heterozygous A>G mutation (c. A1374G) mutation in exon IX, leading to the missense p.N411S in the P450Aro protein and a heterozygous placenta promoter variant -41 base pairs upstream of exon I.1. Aromatase enzyme activity was completely lost when the mutant p.N411S protein was expressed in COS-1 cells. The placenta promoter variant had a significantly reduced (-50%) transactivation ability compared to wild-type.
CONCLUSION: Our data describe a novel loss-of-function missense mutation in CYP19A1 combined with the first-described variant of the placenta promoter with a significant reduction in function, likely to be the molecular basis of this rare 46, XX disorder of sex development. This seems to represent a unique case of aromatase deficiency occurring in utero only.
OBJECTIVE: To better understand this rare disorder, we searched for mutations in the CYP19A1 gene of an affected girl and analysed their functional consequences.
DESIGN AND PATIENT: We examined a girl presenting with clitoral hypertrophy at birth and mild maternal virilization (acne) during pregnancy.
MAIN OUTCOME MEASUREMENT: A genotype-phenotype correlation was found.
RESULTS: By direct sequencing of the CYP19A1 gene, we identified a heterozygous A>G mutation (c. A1374G) mutation in exon IX, leading to the missense p.N411S in the P450Aro protein and a heterozygous placenta promoter variant -41 base pairs upstream of exon I.1. Aromatase enzyme activity was completely lost when the mutant p.N411S protein was expressed in COS-1 cells. The placenta promoter variant had a significantly reduced (-50%) transactivation ability compared to wild-type.
CONCLUSION: Our data describe a novel loss-of-function missense mutation in CYP19A1 combined with the first-described variant of the placenta promoter with a significant reduction in function, likely to be the molecular basis of this rare 46, XX disorder of sex development. This seems to represent a unique case of aromatase deficiency occurring in utero only.